P824: HEMATOLOGIC FEATURES IN 102 FRENCH PATIENTS DIAGNOSED WITH GERMLINE MUTATIONS OF TELOMERES RELATED GENES AGED 15 YEARS OLD OR MORE
Authors: F. Maillet, J.-E. Galimard, R. Borie, C. Kannengiesser, E. Lainey, R. Peffault De Latour, F. Sicre de Fontbrune
Journal: HemaSphere (2022)

Background: Short telomere syndrome (STS) is a group of genetic disorders characterized by germline mutations in telomeres related genes (TRG) leading to premature telomere shortening. In the recent years, the spectrum of STS diseases has widened and now includes heterogeneous associations of hematologic, pneumologic, hepatic and osteoarticular features, and cancer predisposition. STS clinical landscape remain unknown. We took advantage of a large cohort of patients to describe hematologic and extra-hematologic features of this rare disease. Aims: The aim of this study was to describe hematologic and extrahematologic features in patients with STS diagnosed at age 15 or more and followed in adult centers. Methods: All data were obtained from the French National reference Center for Aplastic Anemia. Between 2003 and 2021, we retrospectively included all patients 15 years old or older at diagnosis of STS, with pathogenic germline variant(s) in TRG, and at least one bone marrow assessment (bone marrow aspiration or biopsy). Overall survival (OS) was calculated from date of diagnosis to death or last follow-up using the Kaplan-Meier estimator. Results: One hundred and two patients were included: 89 (87%) were propositus and 13 were diagnosed after genetic counseling. The median follow-up after diagnosis was 3.6 years. The 4 years OS of the index cases was 63% (95% CI: 49 – 74). 62 (70%) and 6 (46%) patients were male, and median age at diagnosis was 42 years (IQR 28-56) and 27 years (IQR 21-48) for index cases and non-index cases, respectively. Median age at onset of first symptoms was 28 years (IQR 20-49) and 29 years (IQR 18-38), with a median duration from first symptoms to STS diagnosis of 5 years (IQR 2-11) and 6 years (IQR 0-7) for index cases and non-index cases, respectively. In index cases, TRG mutations involved TERT in 43 patients (49%), TERC in 24 patients (28%), RTEL1 in 11 patients (13%), DKC1 in 3 patients (3%), and in 1 patient each for NHP2, CTC1, PARN, TINF2, TERT plus TERC (0.9%). In index cases, mutations were heterozygous in 92%, homozygous in 6%, and X-linked in 2%. Among 68 patients with available telomere evaluation, the median telomere length was 6.2% (IQR 4.8-7.4%), whereas the median telomere length at first percentile was 7.6%. Telomere length was shorter than first percentile in 81.5% of patients. 69% of index cases had at least 1 relative with STS. Among index cases, 73 (82%) presented an hematological involvement. At diagnosis, the hematological presentation was BMF in 49 patients (70%), MDS in 17 (24%) and AML in 2 (3%), 1 CVID (1.5%), 1 lymphoma (1.5%) and not specified for 3 patients. During follow-up, evolution toward MDS was observed in 2 patients, and toward AML in 4. 14 patients received allo-HSCT (13.7%): 9 for BMF and 5 for MDS. Extra hematologic features among index cases: 49 patients (55%) had at least one clinical feature of dyskeratosis congenita. Pulmonary involvement was present in 55 patients (62%), of those 93% had diffuse interstitial pneumonia. 12 patients underwent lung transplantation. Hepatic involvement was present in 42 patients (47%), including nodular regenerative hyperplasia (29%), cirrhosis (33%) and portal hypertension (43%). 3 patients underwent liver transplantation. Cancer occurred in 7 patients: 4 solid cancers and 3 lymphomas. Summary/Conclusion: This study in STS patients allows a better understanding of the spectrum of this disease. Hematological presentation was the main feature, followed by lung and hepatic involvement. A long-term multidisciplinary close follow-up is mandatory in this population of patients.